Posts tagged animal model
Articles and news from the latest research reports.
Pregnant mother’s stress affects baby’s gut and brain
Pregnant women may pass on the effects of stress to their fetus by way of bacterial changes in their vagina, suggests a study in mice. It may affect how well their baby’s brain is equipped to deal with stress in adulthood.
The bacteria in our body outnumber our own cells by about 10 to 1, with most of them found in our gut. Over the last few years, it has become clear that the bacterial ecosystem in our body – our microbiome – is essential for developing and maintaining a healthy immune system.
Our gut bugs also help to prevent germs from invading our bodies, and help to absorb nutrients from food.
A baby gets its first major dose of bacteria in life as it passes through its mother’s birth canal. En route, the baby ingests the mother’s vaginal microbes, which begin to colonise the newborn’s gut.
Chris Howerton, then at the University of Pennsylvania in Philadelphia, and his colleagues wanted to know if this initial population of bacteria is important in shaping a baby’s neurological development, and whether that population is influenced by stress during pregnancy.
Stressful pregnancy
The first step was to figure out what features of the mother’s vaginal microbiome might be altered by stress, and then see if any of those changes were transmitted to the offspring’s gut.
To do this, the team exposed 10 pregnant mice to a different psychologically stressful experience, such as exposing them to fox odour, keeping their cages lit at night, or temporarily restraining them every day for what would be the equivalent of the first trimester of their pregnancy. Another 10 pregnant mice were housed normally during the same time.
The team took samples of their vaginal bacteria throughout the pregnancy and again just after the mice had given birth. These samples were genetically sequenced to see what types of bacteria were present.
The microbiomes of the stressed mice were remarkably different to those of the unstressed mice after they had each given birth. There were more types of bacteria present, and the proportion of one common gut bacteria, Lactobacillus, was significantly reduced.
Like mother, like pup
To see whether these changes had been passed on to the pups, a few days after birth the pups’ nascent gut bacteria was removed from their colon and sequenced. Sure enough, the same bacterial patterns were seen in the pups of stressed mothers.
By analysing tissue from the pups’ hypothalamus – a brain area involved in hormone control, behaviour and sleep, among other things – the team was able to infer which genes were affected by the stress-induced changes in each mother’s microbiome.
They found that the expression of 20 genes was affected by the decrease in Lactobacillus, including genes related to the production of new neurons and the growth of synaptic connections in the brain.
These genetic outcomes in the brain are probably a result of a different suite of nutrients and metabolites circulating in the “stressed” pup’s blood, thanks to the altered gut flora they inherited. Indeed, when the team analysed the blood of the pups of the stressed mothers, they found that there were fewer molecules present necessary for the formation of essential neurotransmitters – chemicals that transmit signals to the brain. Furthermore, there were lower levels of a molecule thought to protect the brain from harmful oxidative stress.
"These changes are significant and are likely to be important for determining how the brain initially develops and how it will respond in the future to things like stress or changes in the environment," says Tracy Bale, Howerton’s supervisor during the research and director of the University of Pennsylvania lab.
As well as changing the nutrients available, the microbiome could also affect the brain via the immune system or by innervating the nerves in the gut that connect to it. “These three mechanisms aren’t mutually exclusive. It’s likely that they all play a role,” says Howerton.
Human angle
If the same effects are seen in humans, there may be a straightforward solution. “We can easily manipulate the bacteria we have inside of us,” says Howerton. For example, if a certain cocktail of bacteria is found to be beneficial to the newborns of stressed mothers, we could give it to them right after birth, he suggests. This approach could also benefit babies born via C-section, who do not pass through their mother’s birth canal, or those born to mothers whose gut bacteria has been disrupted as a result of antibiotic use during pregnancy.
Bale is now investigating the link between bacteria and brain development in pregnant women who have been through several traumatic experiences to analyse the effects on their babies’ gut bacteria. She also intends to follow their children’s behaviour as they grow up.
Resource rationale
"This is a remarkable trans-disciplinary study in how it bridged multiple organ systems to illuminate a complex question," says Catherine Hagan from the University of Missouri in Columbia. She says that more work needs to be done to show a causal link. "Mice are not tiny people – people are not big mice – more data is needed to understand how stress in mothers affects brain development in children," she says. "That said, mice and people have enough in common that this study provides a rationale for allocating resources to address such a concern."
"At the end of the day, most of what makes you ‘you’, and what drives your quality of life, comes down to the brain," says Bale. "It’s this very important, vulnerable tissue that is susceptible to many perturbations. If the microbiome is proven to be one of these driving forces, then it’s essential we know just how factors in our environment can change it and can reprogram the brain."
(Source: newscientist.com)
Nicotine withdrawal traced to very specific group of brain cells
Nicotine withdrawal might take over your body, but it doesn’t take over your brain. The symptoms of nicotine withdrawal are driven by a very specific group of neurons within a very specific brain region, according to a report in Current Biology, a Cell Press publication, on November 14. Although caution is warranted, the researchers say, the findings in mice suggest that therapies directed at this group of neurons might one day help people quit smoking.
(Image: Fotolia)
"We were surprised to find that one population of neurons within a single brain region could actually control physical nicotine withdrawal behaviors," says Andrew Tapper of the Brudnick Neuropsychiatric Research Institute at the University of Massachusetts Medical School.
Tapper and his colleagues first obtained mice addicted to nicotine by delivering the drug to mice in their water for a period of 6 weeks. Then they took the nicotine away. The mice started scratching and shaking in the way a dog does when it is wet. Close examination of the animals’ brains revealed abnormally increased activity in neurons within a single region known as the interpeduncular nucleus.
When the researchers artificially activated those neurons with light, animals showed behaviors that looked like nicotine withdrawal, whether they had been exposed to the drug or not. The reverse was also true: treatments that lowered activity in those neurons alleviated nicotine withdrawal symptoms.
That the interpeduncular nucleus might play such a role in withdrawal from nicotine makes sense because the region receives connections from other areas of the brain involved in nicotine use and response, as well as feelings of anxiety. The interpeduncular nucleus is also densely packed with nicotinic acetylcholine receptors that are the molecular targets of nicotine.
It is much less clear whether the findings related to nicotine will be relevant to other forms of addiction, but there are some hints that they may.
"Smoking is highly prevalent in people with other substance-use disorders, suggesting a potential interaction between nicotine and other drugs of abuse," Tapper says. "In addition, naturally occurring mutations in genes encoding the nicotinic receptor subunits that are found in the interpeduncular nucleus have been associated with drug and alcohol dependence."
(Source: eurekalert.org)
FDA-approved immune-modulating drug unexpectedly benefits mice with fatal mitochondrial defect
The transplant anti-rejection drug rapamycin showed unexpected benefits in a mouse model of a fatal defect in the energy powerhouses of cells, the mitochondria. Children with the condition, Leigh syndrome, show progressive brain damage, muscle weakness, lack of coordination or muscle control, and weight loss, and usually succumb to respiratory failure.
Leigh syndrome is often diagnosed within the first year of life. Affected children rarely survive beyond 6 or 7 years. At present, the disorder, which can result from several different underlying causes, has no effective treatment.
Reporting this week in Science Express, UW researchers said that they found that treatment with rapamycin “robustly enhances survival and attenuates disease progression in a mouse model of Leigh’s syndrome.” Given as a daily injection, the drug delayed the onset of neurological symptoms, reduced brain inflammation, and prevented brain lesions.
For most of their lives, the treated mice breathed normally, and did not clasp their legs against their bodies, a posture characteristic of this and related brain disorders in mice. Unlike the untreated mice, they could balance and run on a rotarod, a miniature log rolling exercise toy. Both the median and maximum lifespans within the group of treated mice were strikingly extended, the authors noted.
The median lifespan for this mouse condition is 50 days. In comparison, treated males lived a median of 114 days, and females 111 days. The longest survival in the treated group was 269 days, more than triple that of the untreated animals.
“We were excited at the findings because of the potential impact on treatment for kids with this or related mitochondrial diseases,” said the senior author of the study, Dr. Matt Kaeberlein, UW associate professor of pathology. “Similar intervention strategies might also prove useful for a broad range of mitochondrial diseases or for other conditions resulting from mitochondrial dysfunction.”
Mitochondrial defects lessen the amount of energy available to cells. The depletion can damage or destroy vital tissues. Symptoms and severity of illness depends on which types of cells are affected, but in many cases several organ systems operate poorly as a consequence of malfunctioning mitochondria.
Beyond specific mitochondrial diseases, most of them genetic in origin, the decline or dysfunction of mitochondria contribute to many common health problems, including some forms of heart disease, cancer, and muscle, nerve or brain degeneration associated with aging.
Kaeberlein, who researches factors that lengthen life, has been studying the anti-aging effects of rapamycin for several years. The drug, like calorie-restricting diets, acts by inhibiting mTOR, an abbreviation for the eponymously named mechanistic target of rapamycin.
Kaeberlein said, “This study suggests that this drug’s inhibition of mTOR may have a major impact on mitochondria and energy production in cells. We know that rapamycin appears to slow aging. What we don’t know is whether the effects of rapamycin on mitochondria are a major part of the effects of rapamycin on normal aging and aging-related diseases.”
Alongside their work in aging and lifespan in normal mice, Kaeberlein and his lab decided to study rapamycin’s actions on mice with a severe mitochondrial defect. The mouse model for Leigh syndrome was created in the UW laboratory of Dr. Richard Palmiter, a professor of biochemistry and Howard Hughes Medical Institute investigator who was one of the early originators of transgenic mouse models.
The research team included Dr. Philip G. Morgan and Dr. Margaret M. Sedensky, from the Department of Anesthesiology and Pain Medicine at Seattle Children’s Hospital, who study mitochondrial diseases in patients. The lead scientist was Simon C. Johnson from the UW Department of Pathology.
After seeing unexpected benefits on health and survival, the research group looked closely at the effects on metabolism by examining the levels of more than 100 different metabolites – cellular building blocks and intermediates used to make energy – in the treated and untreated Leigh syndrome mice. The team observed that treated mice appear to burn more amino acids and fats as an energy source, rather than the sugar, glucose. This eliminated the accumulation of glucose breakdown byproducts, including lactate. These byproducts can be toxic and are seen at high levels in human Leigh syndrome patients.
“The drug did not substantially alter mitochondrial composition. Instead, the mice appear to bypass the deficiency in their mitochondria through a shift in their metabolic pattern,” Kaeberlein said. “However, we can’t yet explain exactly how this rescues the mice with Leigh syndrome.”
Because this was a mouse study, evidence of efficacy of rapamycin in Leigh syndrome patients will be a necessary next step. Rapamycin already has FDA approval for several uses, including preventing organ transplant rejection and for treating rare forms of cancer; however, the drug also has side-effects which might limit its utility in very young children. Kaeberlein is optimistic, however, that “even if rapamycin doesn’t turn out to be be useful as a treatment for Leigh Syndrome, the lessons learned here will pave the way to new therapies for this devastating disease.”
Understanding ourselves by studying the animal kingdom
Research released today reveals a new model for a genetic eye disease, and shows how animal models — from fruit flies to armadillos and monkeys — can yield valuable information about the human brain. The findings were presented at Neuroscience 2013, the annual meeting of the Society for Neuroscience and the world’s largest source of emerging news about brain science and health.
Animal models have long been central in how we understand the human brain, behavior, and nervous system due to similarities in many brain areas and functions across species. Almost every major medical advance in the last century was made possible by carefully regulated, humane animal research. Today’s findings build on this rich history and demonstrate what animals can teach us about ourselves.
Today’s new findings show that:
- The nine-banded armadillo may serve as a model for certain types of progressive blindness. The animal’s poor eyesight mimics many human disorders and may shed light on new treatment approaches for such diseases (Christopher Emerling, BS, abstract 150.06, see attached summary).
- Analysis of a baboon population reveals particular genes that may be involved in creating the “folds” in the structure of the brain. These findings provide information on how human genes may have evolved to create the brain’s shape and function (Elizabeth Atkinson, BA, abstract 195.13, see attached summary).
- Monkeys and humans use similar brain pathways while processing decisions. Detailed analyses of similarities and differences in brain wiring could provide new insights into decision-making in humans (Franz-Xaver Neubert, abstract 18.03, see attached summary).
Other recent findings discussed show that:
- Use of powerful genetic tools in fruit flies is helping to reveal the basic building blocks of brain circuitry and function. This work is furthering our understanding of the human brain and may be helpful in developing medical diagnostic devices (Rachel Wilson, PhD, presentation 302, see attached speaker summary).
- Research in a tiny worm (C. elegans) has allowed scientists to map all of the connections between neurons in the species, including the pathways for movement, sex, and more. The findings offer new insights into how the human nervous system functions (Scott Emmons, PhD, presentation 009, see attached speaker summary).
“Neuroscience has always relied on responsible animal research to better understand how our brains and bodies develop, function, and break down,” said press conference moderator Leslie Tolbert, of the University of Arizona, whose work in insects provides insights into brain development. “Today’s studies reveal new ways that research on unlikely-seeming animals, such as armadillos, fruit flies, and worms, could have real impact on our understanding of the human brain and what can go wrong in disease.”
Rats! Humans and rodents face their errors
What happens when the brain recognizes an error? A new study shows that the brains of humans and rats adapt in a similar way to errors by using low-frequency brainwaves in the medial frontal cortex to synchronize neurons in the motor cortex. The finding could be important in studies of “adaptive control” like obsessive compulsive disorder, ADHD, and Parkinson’s.
People and rats may think alike when they’ve made a mistake and are trying to adjust their thinking.
That’s the conclusion of a study published online Oct. 20 in Nature Neuroscience that tracked specific similarities in how human and rodent subjects adapted to errors as they performed a simple time estimation task. When members of either species made a mistake in the trials, electrode recordings showed that they employed low-frequency brainwaves in the medial frontal cortex (MFC) of the brain to synchronize neurons in their motor cortex. That action correlated with subsequent performance improvements on the task.
“These findings suggest that neuronal activity in the MFC encodes information that is involved in monitoring performance and could influence the control of response adjustments by the motor cortex,” wrote the authors, who performed the research at Brown University and Yale University.
The importance of the findings extends beyond a basic understanding of cognition, because they suggest that rat models could be a useful analog for humans in studies of how such “adaptive control” neural mechanics are compromised in psychiatric diseases.
“With this rat model of adaptive control, we are now able to examine whether novel drugs or other treatment procedures boost the integrity of this system,” said James Cavanagh, co-lead author of the paper who was at Brown when the research was done and has since become assistant professor of psychology at the University of New Mexico. “This may have clear translational potential for treating psychiatric diseases such as obsessive compulsive disorder, depression, attention deficit hyperactivity disorder, Parkinson’s disease and schizophrenia.”
To conduct the study, the researchers measured external brainwaves of human and rodent subjects after both erroneous and accurate performance on the time estimation task. They also measured the activity of individual neurons in the MFC and motor cortex of the rats in both post-error and post-correct circumstances.
The scientists also gave the rats a drug that blocked activity of the MFC. What they saw in those rats compared to rats who didn’t get the drug, was that the low-frequency waves did not occur in the motor cortex, neurons there did not fire coherently and the rats did not alter their subsequent behavior on the task.
Although the researchers were able to study the cognitive mechanisms in the rats in more detail than in humans, the direct parallels they saw in the neural mechanics of adaptive control were significant.
“Low-frequency oscillations facilitate synchronization among brain networks for representing and exerting adaptive control, including top-down regulation of behavior in the mammalian brain,” they wrote.
Malignant brain tumours can be transformed into benign forms
Cells of malignant brain tumours deceive our immune system so effectively that it starts working for them. But who lives by the sword, dies by the sword. Researchers from the Nencki Institute in Warsaw show how to deceive brain tumours and change malignant gliomas into benign forms.
The research team of Prof. Bożena Kamińska from the Nencki Institute of Experimental Biology of the Polish Academy of Sciences in Warsaw developed – so far only in animal model – a method of converting malignant gliomas (brain tumours) into benign forms. Since the cells of benign gliomas are subdued and sometimes even eliminated by the host’s immune system, the prospects for survival of sick animals significantly increase. This novel research was funded by the Polish National Science Centre.
The nervous system, including the brain, is inhabited, besides neurons and glial cells, by microglial cells. They support the nervous cells but also have important protective functions, patrolling the surroundings with their extenses and eliminating damaged or unnecessary cells. As macrophages of our immune system they also fight foreign bacteria, viruses and tumorous cells. Unfortunately, sometimes the glia cells themselves become cancerous. This is how brain tumours called gliomas form. However, they are not uniform entity and could differ significantly with respect to their behaviour and degree of malignancy. In benign variants the survival prospects for patients are quite high, while in the case of malignant gliomas few patients are expected to live longer than a year.
In 2007 the group of Prof. Kamińska showed that malignant gliomas can “re-program” the brain immune cells (microglia) to support tumour development instead of fighting it. Similarly the tumour even changed the protective immune cells recruited to the brain from blood and bone marrow (peripheral macrophages). The research to understand how the tumour deceives the host’s immune system and forces the microglial cells to support and foster its growth has taken several years.
The results of other research groups showed that in the case of breast cancer the factor responsible for changing the behaviour of tumour-infiltrating macrophages is the CSF1 protein, controlling the maturation of macrophages. Researchers from the Nencki Institute asked, whether a similar substance is not produces by the cells of the malignant gliomas.
Studies conducted by Prof. Kamińska’s group has shown that gliomas do not produce larger amounts of the CSF1 protein and this protein does not significantly impact tumour development. They were however lucky to discover the production of a different protein from the same family, the CSF2 protein. In benign tumours this protein was present in small amounts, while in malignant gliomas large amounts of it were discovered. Researchers from the Nencki Institute decided to investigate, whether this protein really influences tumour invasiveness. With the help of self-developed tools they turned off the gene responsible for the production of the CSF2 protein in glioma cells.
“We have observed that after turning off a single gene – the gene producing the CSF2 protein – the tumour cells stopped attracting the microglia and were not capable of converting these cells to support the tumour’s development. As a result the immune system started working as expected and the malignant tumour was transformed into a benign form. It did not disappear, but stopped growing”, says a PhD candidate Małgorzata Sielska from the Nencki Institute.
The protein responsible for “re-programming” the anti-tumour response and for high invasiveness of gliomas is present only in cancerous cells and is practically absent from healthy brain. Therefore researchers from the Nencki Institute suspect that when the gene responsible for its production is turned off in the brain, it would affect only the tumour.
Research on taming malignant brain tumours and converting them into benign forms has been conducted on mouse glioma cells growing in the brains of experimental animals, and published in the Journal of Pathology. Presently the group of Prof. Kamińska is checking the effectiveness of this method in the cells of human malignant gliomas. Preliminary results confirm that silencing one gene in human glioma cells growing in mouse brains also stops the growth of the tumour. Developing tools to turn off this gene’s expression, following the creation of appropriate carriers, will in the future open new possibilities for gene therapy in humans.
The findings has helped Nencki researchers develop small molecules (short peptides) which interfere with binding the CSF2 protein (expressed by tumorous cells) to the appropriate receptors on microglial cells. This way the signal coming from tumorous cells gets blocked and the microglia is prevented from “re-programming” itself. The developed molecules, together with relevant genetic tools, are covered by an international patent. Presently researchers work towards starting preclinical and clinical trials of this method.
The proposed solution holds great potential for therapies using small molecules – short peptides or in the case of gene therapy, short RNA silencing gene expression. Will this method really work? This will be confirmed by further experiments and tests. For Nencki researchers it is important that the patented molecules target only one fragment of the signalling pathway which functions between the cells of the malignant tumour and the microglia, thus guaranteeing that no other functions of the organism are affected. Moreover discovery of such an important signalling pathway encourages scientists to search for ways of blocking it in other places, which could be technically more feasible.
“Our research is investigative in nature and above all aims to explain why and how tumours develop. We conducted our research mostly on experimental models, mouse glioma cells or human glioma cells growing in mice. Therefore the road to develop drugs and therapies limiting the invasiveness of gliomas in human is still very long. Luckily we already discovered the molecule that is worth targeting”, sums up Prof. Kamińska.
Experimental Compound Reverses Down Syndrome-Like Learning Deficits In Mice
Researchers at Johns Hopkins and the National Institutes of Health have identified a compound that dramatically bolsters learning and memory when given to mice with a Down syndrome-like condition on the day of birth. As they report in the Sept. 4 issue of Science Translational Medicine, the single-dose treatment appears to enable the cerebellum of the rodents’ brains to grow to a normal size.
The scientists caution that use of the compound, a small molecule known as a sonic hedgehog pathway agonist, has not been proven safe to try in people with Down syndrome, but say their experiments hold promise for developing drugs like it.
“Most people with Down syndrome have a cerebellum that’s about 60 percent of the normal size,” says Roger Reeves, Ph.D., a professor in the McKusick-Nathans Institute of Genetic Medicine at the Johns Hopkins University School of Medicine. “We treated the Down syndrome-like mice with a compound we thought might normalize the cerebellum’s growth, and it worked beautifully. What we didn’t expect were the effects on learning and memory, which are generally controlled by the hippocampus, not the cerebellum.”
Reeves has devoted his career to studying Down syndrome, a condition that occurs when people have three, rather than the usual two, copies of chromosome 21. As a result of this “trisomy,” people with Down syndrome have extra copies of the more than 300 genes housed on that chromosome, which leads to intellectual disabilities, distinctive facial features and sometimes heart problems and other health effects. Since the condition involves so many genes, developing treatments for it is a formidable challenge, Reeves says.
For the current experiments, Reeves and his colleagues used mice that were genetically engineered to have extra copies of about half of the genes found on human chromosome 21.
The mice have many characteristics similar to those of people with Down syndrome, including relatively small cerebellums and difficulty learning and remembering how to navigate through a familiar space. (In the case of the mice, this was tested by tracking how readily the animals located a platform while swimming in a so-called water maze.)
Based on previous experiments on how Down syndrome affects brain development, the researchers tried supercharging a biochemical chain of events known as the sonic hedgehog pathway that triggers growth and development. They used a compound — a sonic hedgehog pathway agonist — that could do just that.
The compound was injected into the Down syndrome-like mice just once, on the day of birth, while their cerebellums were still developing. “We were able to completely normalize growth of the cerebellum through adulthood with that single injection,” Reeves says.
But the research team went beyond measuring the cerebellums, looking for changes in behavior, too. “Making the animals, synthesizing the compound and guessing the right dose were so difficult and time-consuming that we wanted to get as much data out of the experiment as we could,” Reeves says. The team tested the treated mice against untreated Down syndrome-like mice and normal mice in a variety of ways, and found that the treated mice did just as well as the normal ones on the water maze test.
Reeves says further research is needed to learn why exactly the treatment works, because their examination of certain cells in the hippocampus known to be involved in learning and affected by Down syndrome appeared unchanged by the sonic hedgehog agonist treatment. One idea is that the treatment improved learning by strengthening communication between the cerebellum and the hippocampus, he says.
As for the compound’s potential to become a human drug, the problem, Reeves says, is that altering an important biological chain of events like sonic hedgehog would likely have many unintended effects throughout the body, such as raising the risk of cancer by triggering inappropriate growth. But now that the team has seen the potential of this strategy, they will look for more targeted ways to safely harness the power of sonic hedgehog in the cerebellum. Even if his team succeeds in developing a clinically useful drug, however, Reeves cautions that it wouldn’t constitute a “cure” for the learning and memory-related effects of Down syndrome. “Down syndrome is very complex, and nobody thinks there’s going to be a silver bullet that normalizes cognition,” he says. “Multiple approaches will be needed.”
(Source: newswise.com)
Study in mice links cocaine use to new brain structures
Mice given cocaine showed rapid growth in new brain structures associated with learning and memory, according to a research team from the Ernest Gallo Clinic and Research Center at UC San Francisco. The findings suggest a way in which drug use may lead to drug-seeking behavior that fosters continued drug use, according to the scientists.
The researchers used a microscope that allowed them to peer directly into nerve cells within the brains of living mice, and within two hours of giving a drug they found significant increases in the density of dendritic spines – structures that bear synapses required for signaling – in the animals’ frontal cortex. In contrast, mice given saline solution showed no such increase.
The researchers also found a relationship between the growth of new dendritic spines and drug-associated learning. Specifically, mice that grew the most new spines were those that developed the strongest preference for being in the enclosure where they received cocaine rather than in the enclosure where they received saline. The team published its findings online in Nature Neuroscience on August 25, 2013.
"This gives us a possible mechanism for how drug use fuels further drug-seeking behavior," said principal investigator Linda Wilbrecht, PhD, a Gallo investigator now at UC Berkeley, but who led the research while she was on the UCSF faculty.
"It’s been observed that long-term drug users show decreased function in the frontal cortex in connection with mundane cues or tasks, and increased function in response to drug-related activity or information," Wilbrecht said. "This research suggests how the brains of drug users might shift toward those drug-related associations."
In all living brains there is a baseline level of creation of new spines in response to, or in anticipation of, day-to-day learning, Wilbrecht said. By enhancing this growth, cocaine might be a super-learning stimulus that reinforces learning about the cocaine experience, she said.
The frontal cortex, which Wilbrecht called the “steering wheel” of the brain, controls functions such as long-term planning, decision-making and other behaviors involving higher reasoning and discipline.
The brain cells in the frontal cortex that Wilbrecht and her team studied regulate the output of this brain region, and may play a key role in decision-making. “These neurons, which are directly affected by cocaine use, have the potential to bias decision-making,” she said.
Wilbrecht said the findings could potentially advance research in human addiction “by helping us identify what is going awry in the frontal cortexes of drug-addicted humans, and by explaining how drug-related cues come to dominate the brain’s decision-making processes.”
In the first of a series of experiments, the scientists gave cocaine injections to one group of mice and saline injections to another. The next day, they observed the animals’ brain cells using a 2-photon laser scanning microscope. They were surprised to discover that even after the first dose, the mice treated with cocaine grew more new dendritic spines than the saline-treated mice.
In another experiment, they observed the mice before cocaine or saline treatment and then two hours afterward, and discovered that the animals that received cocaine were developing new dendritic spines within two hours after receiving the drug. Furthermore, the next morning, cocaine-induced spines accounted for almost four times more connections among nerve cells than was observed in saline-treated animals.
In a third experiment, the researchers for a week gave the mice cocaine in one distinctive chamber and saline in another, using identical procedures. Each chamber had its own characteristic visual design, texture and smell to distinguish it from the other chamber. They then let the mice choose which chamber to go to.
"The animals that showed the highest quantity of robust dendritic spines – the spines with the greatest likelihood of developing into synapses – showed the greatest change in preference toward the chamber where they received the cocaine," said Wilbrecht. "This suggests that the new spines might be material for the association that these mice have learned to make between the chamber and the drug."
Wilbrecht noted that the research would not have been possible without live brain imaging via the 2-photon laser scanning microscope, which was developed in 2002. “I grew up at the time of the famous public service campaign that showed a pan of frying eggs with the message, ‘this is your brain on drugs,’” recalled Wilbrecht. “Now, with this microscope, we can actually say, ‘this is a brain cell on drugs.’”
(Source: eurekalert.org)
Nicotine exposure gives baby rats addictive personalities
Results suggest explanation for why people exposed to nicotine in the womb are more likely to become smokers.
Exposure to nicotine in the womb increases the production of brain cells that stimulate appetite, leading to overconsumption of nicotine, alcohol and fatty foods in later life, according to a new study in rats.
Smoking during pregnancy is known to alter fetal brain development and increase the risk of premature birth, low birth weight and miscarriage. Prenatal exposure to nicotine also increases the likelihood of tobacco use and nicotine addiction in later life, but exactly how is unclear.
To understand the mechanisms behind this effect, Sarah Leibowitz, a behavioural neurobiologist at the Rockefeller University in New York, and her colleagues injected pregnant rats with small doses of nicotine — which the researchers say are comparable to the amount a pregnant woman would get from smoking one cigarette a day — and then examined the brains and behaviour of the offspring.
In a paper published in Journal of Neuroscience, they found that nicotine increased the production of specific types of neurons in the amygdala and hypothalamus. These cells produce orexin, enkephalin and melanin-concentrating hormone, neuropeptides that stimulate appetite and increase food intake.
Rats exposed to nicotine in the womb had more of these cells and produced more of the neuropeptides than those that were not, and this had long-term consequences on their behaviour. As adolescents, they not only self-administered more nicotine, but also ate more fat-rich food and drank more alcohol.
“These peptide systems stimulate food intake,” says Leibowitz, “but we found that they similarly increase the consumption of drugs and stimulate the brain’s reward mechanisms that promote addiction and substance abuse.”
Leibowitz notes that children whose mothers smoked during pregnancy are more likely to smoke themselves during adolescence and adulthood. Her team’s findings suggest a possible mechanism for that.
The use of nicotine patches or e-cigarettes during pregnancy could have a similar effect. “Whether given subcutaneously, as in our study, or via smoking or patches, the same amount of nicotine would still get into the brain to affect neuronal development and function,” Leibowitz says.
The results highlight the toxic effects of nicotine exposure on brain development, says George Koob, a neurobiologist at the Scripps Research Institute in La Jolla, California. He also adds that the study casts new light on the role of these neuropeptides in reward and motivation.
In earlier work, Leibowitz and her colleagues showed that rats exposed to fat and alcohol in the womb likewise overconsume these substances as adolescents. “Our studies make it very clear that neuronal development in utero is highly sensitive to these substances,” she says, “with each promoting their overconsumption and addictive-like behaviour in the offspring.”
She and her collaborators are now comparing the effects of nicotine, fat and alcohol to learn more about how this promotion occurs. They are also exploring ways to reverse the effects of prenatal exposure to these substances, thus preventing their overconsumption in later life, which could lead to addiction and obesity.
Omega-3 removes ADHD symptoms
A new multidisciplinary study shows a clear connection between the intake of omega-3 fatty acids and a decline in ADHD symptoms in rats.
Researchers at the University of Oslo have observed the behaviour of rats and have analyzed biochemical processes in their brains. The results show a clear improvement in ADHD-related behaviour from supplements of omega-3 fatty acids, as well as a faster turnover of the signal substances dopamine, serotonin and glutamate in the nervous system. There are, however, clear sex differences: a better effect from omega-3 fatty acids is achieved in male rats than in female.
Unknown biology behind ADHD
Currently the psychiatric diagnosis ADHD (Attention Deficit/Hyperactivity Disorder) is purely based on behavioural criteria, while the molecular genetic background for the illness is largely unknown. The new findings indicate that ADHD has a biological component and that the intake of omega-3 may influence ADHD symptoms.
“In some research environments it is controversial to suggest that ADHD has something to do with biology. But we have without a doubt found molecular changes in the brain after rats with ADHD were given omega-3,” says Ivar Walaas, Professor of Biochemistry.
The fact that omega-3 can reduce ADHD behaviour in rats has also been indicated in previous international studies. What is unique about the study in question is a multidisciplinarity that has not previously been seen, with contributions from behavioural science in medicine as well as from psychology, nutritional science and biochemistry.
Hyperactive rats
The rats used in the study are called SHR rats – spontaneously hypertensive rats. Although this is primarily a common type of rat, random mutations in their genes have resulted in genetic damage that produces high blood pressure. It is therefore first and foremost blood-pressure researchers who have so far been interested in these rats.
However, the rats do not suffer from high blood pressure until they have reached puberty. Before that age they present totally different symptoms – namely hyperactivity, poor ability to concentrate and impulsiveness. It is exactly these three criteria that form the basis for making the ADHD diagnosis in humans. The animals also react to Ritalin, the central nervous system stimulant, in the same way as humans with ADHD: the hyperactive responses are stabilized. SHR rats are therefore increasingly used in research as a model for ADHD.
Supplements as early as the foetal stage
Researchers believe that omega-3 can have an effect from the very beginning of life. Omega-3 was therefore added to the food given to mother rats before they were impregnated, and this continued throughout their entire pregnancy and while they fed their young. The baby rats were also given omega-3 in their own food after they were separated from their mother at the age of 20 days. Another group of mother rats were given food that did not have omega-3 added, thus creating a control group of SHR offspring that had not been given these fatty acids at the foetal stage or later.
The researchers started to analyze the behaviour of the offspring some days after they were separated from the mother. They studied behaviour driven by reward as well as spontaneous behaviour. Substantial differences were noted for both types of behaviour between the rats that had been given the omega-3 supplement as foetuses and as baby rats and those that had not.
Rewards made male rats more concentrated
The reward-driven behaviour was such that the rats were allowed access to a drop of water each time they pressed an illuminated button. The ADHD rats that had not been given omega-3 could not concentrate on pressing the button, whereas the rats that had been brought up on omega-3 easily managed to hold their concentration for the seconds this takes and were able to enjoy a delicious drop of water as a reward.
Surprisingly enough, it was only male rats that showed an improvement in reward-driven behaviour. However, with regard to the rats’ spontaneous behavior, the same type of reduction in hyperactivity and attention difficulties was noted in both male and female rats that had been given the omega-3 supplement.
Changes in brain chemistry
Professor Walaas and his research group became involved in the study at this point in order to analyze the molecular processes in the rats’ brains.
The group analyzed the level of the chemical connections in the brain, the so-called neurotransmitters that transfer nerve impulses from one nerve cell to another. The researchers measured how much of the neurotransmitters such as dopamine, serotonin and glutamate was released and broken down within the nerve fibres. A key player in this work was Kine S. Dervola, PhD candidate, who reports clear sex differences in the turnover of the neurotransmitters – just as there had been in the reward-driven behaviour.
“We saw that the turnover of dopamine and serotonin took place much faster among the male rats that had been given omega-3 than among those that had not. For serotonin the turnover ratio was three times higher, and for dopamine it was just over two and a half times higher. These effects were not observed among the female rats. When we measured the turnover of glutamate, however, we saw that both sexes showed a small increase in turnover,” Ms Dervola tells us.
Transferrable to humans?
The researchers are cautious about drawing conclusions as to whether the results can be transferred to humans.
“In the first place there is of course a difference between rats and humans, and secondly the rats are sick at the outset. Thirdly the causes of ADHD in humans are in no way mapped sufficiently well. But the end result of what takes place in the brains of both rats and humans with ADHD is hyperactivity, poor ability to concentrate and impulsiveness,” says Professor Walaas, and concludes:
“Giving priority to basic research like this will greatly increase our detailed knowledge of ADHD.”
Reference:
Dervola, Kine-Susann Noren; Roberg, Bjørg Åse; Wøien, Grete; Bogen, Inger Lise; Sandvik, Torbjørn; Sagvolden, Terje; Drevon, Christian A, Espen B. Johansen and Sven Ivar Walaas (2012). Marine omega-3 polyunsaturated fatty acids induce sex-specific changes in reinforcer-controlled behavior and neurotransmitter metabolism in a spontaneously hypertensive rat model of ADHD. Behavioral and Brain Functions. ISSN 1744-9081. 8(56).
(Source: med.uio.no)